Triterpenoids comprise a class of natural products that are reported to have medicament properties including anti-ulcer, anti-inflammatory, anti-allergy, anti-hepatitis and antiviral activities. As shown below, some examples of this class of molecules exhibit a ring structure having either 5 six membered rings, or 4 six membered rings and one five membered ring. Members of this latter classification are termed lupanes.
Perhaps one of the most studied of the triterpenoids is glycyrrhetinic acid, shown below, and derivatives thereof. For instance, certain glycyrrhetinic acid derivatives can prevent or heal gastric ulcers. Doll, R. et al., Lancet 11: 793 (1962). Among such compounds known in the art are carbenoxolone (U.S. Pat. No. 3,070,623), glycyrrhetinic acid ester derivatives having substituents at the 3-O position (U.S. Pat. No. 3,070,624), amino acid salts of glycyrrhetinic acid (Japanese Patent Publication JP-A-44-32798), amide derivatives of glycyrrhetinic acid (Belgian Patent No. 753773), amide derivatives of 11-deoxoglycyrrhetinic acid (British Patent No. 1346871), cicloxolone (Journal of Antimicrobial Chemotherapy, 18:B: 1845-200(1986), and glycyrrhizic acid and its derivatives (Chem. Pharm. Bull. 39(1): 112-115), (1991).
Additionally, U.S. Pat. No. 3,934,027 shows 18-.beta.-glycyrrhetinic acid amides that are useful as antiulcer agents. U.S. Pat. No. 4,173,648 shows 3-.beta.-hydroxy-18-.beta.-olean-9-en-3O-oic acids also for treating ulcers.
Finally, WO 93/09129 describes certain triterpene compounds that exhibit anti-inflammatory activity. ##STR2##
Triterpenoids that exhibit a ring structure having 4 six membered rings and one five membered ring, are termed lupanes. Betulinic acid, a member of this class of natural products, has the following structure: ##STR3##
Similar to other triterpenoids, betulinic acid is known to have certain medical applications, including use as an anticancer drug. See, for example, JP 87,301,580. Anti-cancer applications are premised on the observation that cells require an adequate level of polyamines to grow at an optimal rate, and that cell growth can be inhibited by drugs that interfere with the enzymatic synthesis of polyamines. Four enzymes are known to be involved in the synthesis of polyamines: ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Heby, O., Adv. Enzyme Regul., 24: 103-124, (1985). The activities of the two decarboxylases are rate limiting, and betulinic acid is a known inhibitor of ornithine decarboxylase. Yasukawa, K. et al. Oncology 48: 72-76 (1991). Its capacity to inhibit ornithine decarboxylase is, at least in part, responsible for its anti-cancer activity.
Although there have been some studies on the derivization of triterpenoids, particularly as related to glycyrrhetinic acid, as discussed above, little work has been done describing derivatives of betulinic acid. Choi et al have shown that betulinic acid 3-monoacetate, and betulinic acid methyl ester exhibit ED.sub.50 values of 10.5 and 6.8 ug/ml, respectively, against P-388 lymphocytic leukemia cells. Choi, Y-H et al., Planta Medica vol. XLVII, pages 511-513, (1988).
It will be appreciated that because of the medicament properties of betulinic acid, it would be desirable to identify regions of the molecule that could be chemically modified in order to synthesis analogues or derivatives that are active against a wider spectrum of cancers, or that can be used to treat diseases other than cancer.
The lupanes, and specifically betulinic acid, have been reported to be effective anti-inflammatory agents. The anti-inflammatory activity of betulinic acid is, at least in part, due to its capacity to inhibit enzymes involved in leukotriene biosynthesis, including 5-lipoxygenase. Sotomatsu, S., et al., Skin and Urology 21: 138 (1959) and Inoue, H., et al., Chem. Pharm. Bull. 2: 897-901 (1986). Thus, a further reason to identify new betulinic acid derivatives is to take advantage of betulinic acids multi-medicament properties, and to produce medicaments that can be used to treat different diseases.